1. Field of the Invention
The present invention relates to carbapenem derivatives which have potent antimicrobial activity against a wide range of bacteria. More particularly, the present invention relates to novel carbapenem derivatives which have a substituted or unsubstituted imidazo[5,1-b]thiazole or imidazo[5,1-b]thiazolium group at the 2-position of the carbapenem ring through a pyrrolidinylthio group.
2. Background Art
Carbapenem derivatives, by virtue of potent antimicrobial activity against a wide spectrum of bacteria, have been energetically studied as a highly useful .beta.-lactam agent, and Imipenem, Panipenem, and Meropenem have been clinically used.
At the present time, both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 ("DHP-1") in the case of Impenem and in order to reduce nephrotoxicity in the case of Panipenem. On the other hand, Meropenem, which has been recently put on the market, has increased stability against DHP-1 by virtue of the presence of a methyl group at the 1.beta.-position and hence enabled the use as a single active ingredient in medicaments.
However, the stability against DHP-1 is not yet satisfactory. Further, the antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and resistant Pseudomonas aeruginosa which have risen a serious clinical problem these days are also not always satisfactory. It is therefore strongly demanded to obtain novel carbapenem antibiotics which have improved antimicrobial activity against these bacteria.
WO 96/028455 discloses that carbapenem derivatives having an aromatic heterocyclic imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring have antimicrobial activity.
Japanese Patent Laid-Open Nos. 239058/1993 and 291973/1995, WO 95/10520, and WO 93/21186 disclose carbapenem derivatives wherein the 5-position of a pyrrolidinylthio group bonded to the 2-position of the carbapenem ring is bonded to the carbon atom on the aromatic heterocycle through a suitable spacer. None of these publications disclose carbapenem derivatives bonded to a bicyclic aromatic heterocycle.